Process for the preparation of 4-(acylsulfamyl) derivatives of anilic acids



action products.

Patented Aug. 11 195 3 UNITED STATES oFFlcE,

$648,690 R SS F R TH R ARA IQ 0F '41- KAQY SU -FA ATIVES Q @NIIJQAC I Evan J. Young, Valley Park, M9" assi n!!! l9 M931? sant Qhemina aeration a t-9e! many, atnris are! No llravving. Application December w, 195 0,

" Q IElF -W H wherein A represents an acyl radical derived mm an aliphatic n t l iacid and B dicarboxylic acid.

The above described derivatives have widespread utility as pharmaceuticals. Heretofore, they have been prepared by jrea cting' aif 2N acylsulfanilamide, wherein the acy1'\ radical derived from an aliphatic monocarboxylic laci d, with a dicarboxylicacid anhydride in an al'c'o' hol solution orpther inert soivent. .ln g this-reaction did not proceed satisfactoril I result of which the yield ofthe desired an c acid derivative was relatively low and the product had to be submitted to difiicult purification procedures to eliminate unreacted products and highly colored by-products. It is an objectof thisinvention, therefore, to provide an improved process for the preparation of the above, deib -iatylsuliam der va ves .O ar i acids by-the reaction of an'N eacylsulfanilamide represents a monoacyl radicahderived from a and a diearboxylic acid anhydride.

It has now been discovered that highly improvedyields of thesederivativesas he b acylsulfanilamide wherein the gamma derived from an aliphatic monocarho gylio acid and a dicarboxylic acid anhydride in la ketone selected from the group'pqt fii fiing,Qf ,aCQtone and 2-butanone. It has further been-found that from the reaction mixture obtained in accordance with the novel process of this invention, the

anilic=.acid derivative may conveniently .be 'recovered in a substantially lpure state as a white crystalline material having no foreign odor and substantially free of any highly coloredyside re- The following examples are descmbedin lqlxamp I) I constanta tation th resul an olu n was bOi1.ed.-1l1ld reflux c ditions (57 C.-. o ppr x mately two hou s, after which ti th excess acetone was remoredzb d sti lat o until a'lthick paste re ained. To thi reacti mass 8.09 parts of wat rv were th n dded and th sultant' slurry filtered- The te k washed several, times 7 with water and then dried bylheating touatemperatureof l0 5 C. 8 6 parts f 4':-(acety1sulfamyl) nhth lanilic acid er Obtained, rep esentin a1.9% ..yi ?-.l 9.4;- acetylsul-famyl) mphthalani i aqid thu ob ined was a white crystalline material, ireejrornforeign odor .and havin a melting p in of 1.9 198 to. i I I quality to that obtained'iifil lxarnpleli I -4 acetytsuZfa rtg/Z) succinanilic acid ri ea q acid thus obtained "is comparable in yield' and .nce with the procedure described in le I fan,eiicellentyield *of sutsta' 11y acetylsulfa'riiyl) succinanilic acid is b v I tilizifig" 5'3jl6 "p rts of "N f-acetyls'ul fa ilam e," 28 artsof succlnic'"anhydfideand;400 ig ip hqgt e i4- (tpropion ylsulyianzyl) adipanzlic acid 1 Utili m 57 a a ti Ni-propionylsulfanil d 36 ipiclanhydride and A00 parts partsof at z butanoneinjfac illustrative of the novel process of this invention, whereiniall parts .are Jay-L weight unless otherwise noted:

EXAMPLE I 4'-(acetylsulfamyl) phthe lq' r z flz'c g c id To a solution of 53.6 parts (0.25 mol) of N acetyl sulfanilamide in 400 parts of acetone was ried' out by boilmg the reaction "mixture "u'rider reflux conditions.

The quantities of the reactants utilized may also be varied over a substantial range. Since the reaction between the sulfanilamide derivative and the dicarboxylic acid anhydrid is substantially quantitative, it is preferred that approximately equimolecular proportions of these reactants be utilized. In excess of a one molecular proportion of the dicarboxylic acid anhydride for each one molecular proportion of the sulfanilamide derivative may be utilized if desired with- I ants which is fluid at the reaction temperatures I and capable of proper agitation.

In carrying out the novel process of this invention, any N -acylsulfanilamide, wherein the acyl derivative is derived from an aliphatic substituted or unsubstituted monocarboxylic acid, may be utilized. Typical of such derivatives are the N -acetylsulfanilamide, N -propionylsulfanilamide, N -valerylsulfanilamide, N -phenylacetylsulfanilamide, N chloroacetylsulfanilamide. Similarly any of the dicarboxylic acid anhydrides may be utilized in the novel process of this invention. Typical of such anhydrides are the anhydrides of maleic acid, succinic acid, gammaketopimeli-c acid, sebacic acid, phthalic acid, chlorophthalic acid, etc.

After the reaction as above described is complete, the desired 4-acylsulfamyl derivative of the anilic acid may be recovered from the reaction mixture by any method well known to those skilled in the art. Preferably, the desired derivative is recovered by first removing the ketone solvent, diluting the reaction mass thus obtained with water, and then filtering it to recover the desired derivative which may then be further purified if desired.

What is claimed is:

1. In a process for the preparation of 4-(acylsulfamyl) derivatives of anilic acids, the step comprising reacting an N -acylsulfanilamide, wherein the acyl radical is derived from a monocarboxylic acid by the removal of the hydroxyl group, said monocarboxylic acid being selected from the group consisting of saturated alkyl monocarboxylic acids containing 2 to 5 carbon atoms inclusive and phenylacetic acid, and a dicarboxylic acid anhydride selected from the group consisting of the anhydrides of saturated alkyl dicarboxylic acids containing 4 to 10 carbon atoms inclusive, maleic acid, gamma-ketopimelic acid, phthalic acid and chlorophthalic acid in a ketone selected from the group consisting of acetone and 2-butanone.

2. In a process for the preparation of 4'-(acetylsulfamyl) phthalanilic acid, the step comprising reacting an N -acetylsulfanilamide and phthalic anhydride in a ketone selected from the group consisting of acetone and Z-butanone.

3. The process as described in claim 2 wherein the ketone is acetone.

' 4. In a process for the preparation of 4-(acetylsulfamyl) succinanilic acid, the step comprising reacting an N -acetylsulfanilamide and succinic anhydride in a ketone selected from the group consisting of acetone and 2-butanone.

5. The process as described in claim 4 wherein the ketone is acetone.

6. In a process for the preparation of 4-(acylsulfamyl) derivatives of anilic acids, the step comprising reacting an N -acylsulfanilamide, wherein the acyl radical is derived from a monocarboxylic acid by the removal of the hydroxyl group, said monocarboxylic acid being selected from the group consisting of saturated alkyl monocarboxylic acids containing 2 to 5 carbon atoms inclusive and phenylacetic acid, and a dicarboxylic acid anhydride selected from the group consisting of the anhydrides of saturated alkyl dicarboxylic acids containing 4 to 10 carbon atoms inclusive, maleic acid, gamma-ketopimelic acid, phthalic acid and chlorophthalic acid in a ketone selected from the group consisting of acetone and 2-butanone while boiling the reaction mixture under reflux conditions.

'7. In a process for the preparation of 4-(acylsulfamyl) derivatives of anilic acids, the step comprising reacting a one molecular proportion of N -acylsulfanilamide, wherein the acyl radical is derived from a monocarboxylic acid by the removal of the hydroxyl group, said monocarboxylic acid being selected from the group consisting of saturated alkyl monocarboxylic acids containing 2 to 5 carbon atoms inclusive and phenylacetic acid, and approximately a one molecular proportion of a dicarboxylic acid anhydride selected from the group consisting of the anhydrides of saturated alkyl dicarboxylic acids containing 4 to 10 carbon atoms inclusive, maleic acid, gamma-ketopimelic acid, phthalic acid and chlorophthalic acid in a ketone selected from the group consisting of acetone and 2-butanone, while boiling the reaction mixture under reflux conditions.

8. In a process for the preparation of 4'-(acetylsulfamyl) phthalan-ilic acid, the step comprising reacting a one molecular proportion of N acetylsulfanilamide and approximately a one molecular proportion of phthalic anhydride in a ketone selected from the group consisting of acetone and 2-butanone, while boiling the reaction mixture under reflux conditions.

9. The process as described in claim 8 wherein the ketone is acetone.

10. In a process for the preparation of 4-(acetylsulfamyl) succinanilic acid, the step comprising reacting a one molecular proportion of N acetylsulfanilamide and approximately a one molecular proportion of succinic anhydride in a ketone selected from the group consisting of acetone and 2-butanone, while boiling the reaction mixture under reflux conditions.

11. The process as described in claim 10 wherein the ketone is acetone.

EVAN J. YOUNG.

References Cited in the, file of this patent I FOREIGN PATENTS Number V v Country Date 557,985 Great Britain Dec. 14, 1943 595,018 Great Britain Nov. 25, 1947 OTHER REFERENCES 

1. IN THE PROCESS FOR THE PREPARATION OF 4-(ACYLSULFAMYL) DERIVATIVES OF ANILIC ACIDS, THE STOP COMPRISING REACTING AN N1-ACYLSULFANILAMIIDE. WHEREIN THE ACYL RADICAL IS DERIVED FROM A MONOCARBOXYLIC ACID BY THE REMOVAL OF THE HYDROXYL GROUP, SAID MONOCARBOXYLIC ACID BEING SETTLED FROM THE GROUP CONSISTING OF SATURATED ALKYL MONOCARBOXYLIC ACIDS CONTAINING 2 TO 5 CARBON ATOMS INCLUSIVE AND PHENYLACETIC ACID, AND A DICARBOXYLIC ACID ANHYDRIDE SELECTED FROM THE GROUP CONSISTING OF THE ANHYDRIDES OF SATURATED ALKYL DICARBOXYLIC ACIDS CONTAINING 4 TO 10 CARBON ATOMS INCLUSIVE, MALEIC ACID, GAMMA-KETOPIMELIC ACID, PHTHALIC ACID AND CHLOROPHTHALIC ACID IN A KETONE SELECTED FROM THE GROUP CONSISTING OF ACETONE AND 2-BUTANONE. 